Coactivation of Estrogen Receptor and IKKβ Induces a Dormant Metastatic Phenotype in ER-Positive Breast Cancer

A growing body of evidence suggests that the inflammatory NF kappa B pathway is associated with the progression of ER+ tumors to more aggressive stages. However, it is unknown whether NF kappa B is a driver or a consequence of aggressive ER+ disease. To investigate this question, we developed breast cancer cell lines expressing an inducible, constitutively active form of IkB kinase beta (CA-IKK beta), a key kinase in the canonical NF kappa B pathway. We found that CA-IKK beta blocked E2-dependent cell proliferation in vitro and tumor growth in vivo in a reversible manner, suggesting that IKK beta may contribute to tumor dormancy and recurrence of ER+ disease. Moreover, coactivation of ER and IKK beta promoted cell migration and invasion in vitro and drove experimental metastasis in vivo. Gene expression profiling revealed a strong association between ER and CA-IKK beta-driven gene expression and clinically relevant invasion and metastasis gene signatures. Mechanistically, the invasive phenotype appeared to be driven by an expansion of a basal/stem-like cell population rather than EMT. Taken together, our findings suggest that coactivation of ER and the canonical NF kappa B pathway promotes a dormant, metastatic phenotype in ER+ breast cancer and implicates IKK beta as a driver of certain features of aggressive ER+ breast cancer. Significance: The canonical NF kappa B pathway promotes expansion of stem/basal-like cells and a dormant, metastatic phenotype in ER+.